Development of Low-Molecular-Weight Compounds Targeting the Cancer-Associated KLF5 Transcription Factor

Krüppel-like
factor 5 (KLF5) is a potential target for anticancer
drugs. However, as an intrinsically disordered protein (IDP) whose
tertiary structure cannot be solved, innovative strategies are needed.
We focused on its hydrophobic α-helix structure, defined as
an induced helical motif (IHM), which is a possible interface for
protein–protein interaction. Using mathematical analyses predicting
the α-helix’s structure and hydrophobicity, a 4-amino-acid
site (V-A-I-F) was identified as an IHM. Low-molecular-weight compounds
that mimic the main chain conformation of the α-helix with the
four side chains of V-A-I-F were synthesized using bicyclic pyrazinooxadiazine-4,7-dione.
These compounds selectively suppressed the proliferation and survival
of cancer cells but not noncancer cells and decreased the protein
but not mRNA levels of KLF5 in addition to reducing proteins of Wnt
signaling. The compounds further suppressed transplanted colorectal
cancer cells in vivo without side effects. Our approach
appears promising for developing drugs against key IDPs.